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1.
Braz J Psychiatry ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33825765

RESUMO

CLINICAL TRIAL REGISTRATION: Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

2.
Am J Psychiatry ; : appiajp202020050653, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33653118

RESUMO

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

3.
J Affect Disord ; 286: 320-329, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33770540

RESUMO

BACKGROUND: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response. METHODS: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations. RESULTS: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01). LIMITATIONS: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available. CONCLUSIONS: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.

4.
Transl Psychiatry ; 11(1): 88, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526782

RESUMO

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

6.
Neuropsychopharmacology ; 46(4): 820-827, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33318635

RESUMO

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-D-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33249434

RESUMO

BACKGROUND: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure which modulates reward and affective states. METHODS: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with intravenous ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. RESULTS: A reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 24 hours after ketamine infusion was associated with an increase in FC between the right Hb and a cluster in the right frontal pole (t=4.65, P=0.03, FDR-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t=5.18, p<0.0001, FDR-corrected), right temporal pole (t=4.97, P<0.0001, FDR-corrected), right parahippocampal gyrus (t=5.80, P=0.001, FDR-corrected), and left lateral occipital cortex (t=4.73, P=0.03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. CONCLUSIONS: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

9.
Adv Pharmacol ; 89: 131-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616205

RESUMO

Major depressive disorder (MDD) is a debilitating illness with significant morbidity and mortality, leading to attempted and completed suicides. It affects interpersonal relationships and also contributes to decreased productivity, causing financial burden to individuals and society. Patients often fail to respond to various antidepressant medication trials resulting in treatment-resistant depression (TRD). Current antidepressant medications work by modulating the monoaminergic systems and takes several weeks to establish a clinical response. Ketamine has been used extensively as an anesthetic agent since the 1970s, and more recent research has shown its rapid and robust effectiveness in TRD the subject of this review. Ketamine is a racemic mixture comprised of two enantiomers (R)-ketamine and (S)-ketamine and acts as an NMDA receptor antagonist. Most research studies have explored its antidepressant and antisuicidal effects by using it as an intravenous infusion or via the intranasal route due to increased bioavailability. Recently an intranasal esketamine spray was approved by the United States Food and Drug Administration (FDA) for TRD as an adjunct to standard antidepressant treatment in a supervised setting. Regarding its safety profile, multiple research studies have established the short-term safety and efficacy of ketamine in TRD. The cardiorespiratory and neuropsychiatric adverse events observed in these studies were mostly transient. However, ketamine is a scheduled agent with abuse potential, making its long-term use challenging and mandating further research.


Assuntos
Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Antidepressivos/uso terapêutico , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de N-Metil-D-Aspartato/metabolismo , Suicídio
10.
Neuropsychopharmacology ; 45(10): 1656-1663, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544925

RESUMO

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

11.
J Affect Disord ; 273: 318-327, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421619

RESUMO

BACKGROUND: Emerging literature suggests that the arousal and regulatory systems as measured by sleep-wakefulness, heart rate (HR) and heart rate variability (HRV) may be powerful objective warning signs of suicidality. However, there is no systematic literature review examining the association between objective measurements of these variables with suicide and suicidal behavior. METHODS: A web-based, systematic literature search using PubMed and EMBASE was conducted for articles that measured sleep-wakefulness and HR/HRV quantitatively in association with suicide. Search results were limited to human subjects and articles published in peer-reviewed journals in English. There were no restrictions for age, sex, settings and durations of measurements, types of mental illnesses, or comorbidity. RESULTS: Twenty-three studies were included in the current systematic review. Across the studies, consistent patterns of disturbed sleep-wakefulness such as greater sleep onset latency and lower sleep efficiency were related to suicide. In addition, higher HR and lower variance of R-R intervals was an indicator of risk of suicide. LIMITATIONS: Studies that used different equipment for sleep studies (i.e., polysomnography, electroencephalogram, actigraphy) were combined, and potential differences in their findings due to the different equipment were not considered. CONCLUSIONS: Findings provide initial evidence for consistent patterns of sleep-wakefulness and HR/HRV possibly associated with suicidality; however, more studies are needed in order to identify the precise objective variables (e.g., sleep onset latency, high-frequency HRV), as well as time-varying patterns in these variables, that are related to acute suicide risk.

12.
J Clin Psychiatry ; 81(4)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32459407

RESUMO

OBJECTIVE: Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES: A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/uso terapêutico , Administração Intranasal , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quimioterapia Combinada/métodos , Humanos , Ketamina/administração & dosagem , Resultado do Tratamento
13.
Curr Top Behav Neurosci ; 47: 179-195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32472429

RESUMO

Suicide is the leading cause of injury mortality in the United States and the second-leading cause of death in people aged 10-34 years. While many long-term risk factors are known, the short-term prediction of suicidal behavior remains elusive. Many characteristics of suicidal behavior cut across diagnoses, but suicide is increased in recurrent psychiatric disorders, addictive disorders, and trauma-related disorders. Suicide results from the interaction of short-term and long-term behavioral regulation. The shorter the time-course of the mechanism, the closer it is to actual suicidal behavior, and the harder it is to prevent. We will discuss the manner in which impulsivity, a major determinant of short-term suicide risk, interacts with longer-term risk factors, especially sensitization to addictive or traumatic stimuli. Impulsivity predisposes to sensitization; in turn, impulsivity is a prominent component of sensitized behavior. Impulsivity can be described as a general pattern of behavior ("trait" impulsivity), as responses that are not conformed to their context (action-impulsivity), or as inability to delay reward or to take future consequences into account (choice-impulsivity). Each of these contributes to suicidal behavior. The neural mechanisms of impulsivity and sensitization are analogous, and sensitization can produce rapidly fluctuating patterns of impulsive behavior, arousal, and anhedonia. In order to recognize and prevent suicidal behavior, it is necessary to identify factors associated with susceptibility to bouts of impulsive behavior in people at elevated long-term risk.


Assuntos
Tentativa de Suicídio , Suicídio , Adolescente , Adulto , Anedonia , Criança , Humanos , Comportamento Impulsivo , Recompensa , Adulto Jovem
14.
J Clin Psychopharmacol ; 40(3): 287-292, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32332464

RESUMO

PURPOSE/BACKGROUND: Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression. METHODS/PROCEDURES: Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed. FINDINGS/RESULTS: The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion. IMPLICATIONS/CONCLUSIONS: Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity. CLINICAL TRIAL REGISTRATION: NCT01920555.

15.
Nat Med ; 26(5): 760-768, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231295

RESUMO

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.


Assuntos
Anedonia/efeitos dos fármacos , Benzamidas/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Antagonistas de Entorpecentes/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores Opioides kappa/antagonistas & inibidores , Adulto , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/psicologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Transtornos do Humor/psicologia , Estudo de Prova de Conceito , Fatores de Tempo , Resultado do Tratamento
17.
Psychiatr Clin North Am ; 43(1): 199-211, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008685

RESUMO

Treatment guidelines for mixed states of depression or (hypo)mania focus almost exclusively on psychopharmacologic intervention without tapping into the benefits of psychotherapy. The authors highlight the complex clinical picture and illness course of mixed states, and discuss the benefit of taking a patient-centered approach to treatment incorporating techniques from a variety of evidence-based psychotherapies. A careful assessment of suicide risk as well as interventions designed specifically for anxiety are also recommended.


Assuntos
Transtorno Bipolar/terapia , Transtorno Depressivo Maior/terapia , Psicoterapia , Adulto , Ansiedade/terapia , Feminino , Humanos , Escalas de Graduação Psiquiátrica , Ideação Suicida
18.
Mol Psychiatry ; 25(7): 1592-1603, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-30283029

RESUMO

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

19.
Mol Psychiatry ; 25(7): 1604, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617276

RESUMO

Supplementary Figure 1 and Supplementary Tables 1-4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.

20.
Psychophysiology ; 57(1): e13356, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30807663

RESUMO

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p < 0.05). While all PTSD participants showed typical impairments in fear inhibition prior to treatment, GSK561679 enhanced fear inhibition post-treatment, independent of clinical effects. The current study suggests that CRF receptor 1 antagonism may have specific effects within neural circuitry mediating fear inhibition responses, but not overall symptom presentation, in PTSD.

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